Allergic asthma is a chronic respiratory disease characterized by airway inflammation, excessive mucus production, reversible airway obstruction, and airway hyperreactivity (AHR) (Lazaar and Panettieri, 2004). The aetiopathogenesis of allergic asthma is complex and encompasses the interplay between genetic predisposition, environmental triggers and dysregulated immune response (Lazaar and Panettieri, 2004, Lukacs, 2001). The precise mechanism of chronic airway inflammation that characterizes persistent asthma remains elusive, but appears to result from a strongly allergen-driven type 2-skewed CD4+ T helper (Th2) lymphocyte infiltration of the airways with the induction of Th2 cytokines interleukin (IL)-4, IL-5, IL-13 and IL-25 (Lazaar and Panettieri, 2004). These cytokines function in concert with CC chemokines (such as eotaxins and thymus and activation-regulated chemokines) and, to a lesser extent, CXC chemokines and result in the recruitment and activation of eosinophils and IgE production (Lazaar and Panettieri, 2004, Lukacs, 2001). Infiltration of eosinophils and other inflammatory cells in the lower respiratory tract is the hallmark of allergic asthma, and may be important in the pathogenesis of this disease (Lazaar and Panettieri, 2004, Lukacs, 2001). Besides allergic asthma, there are many other diseases and disorders that are thought to be caused or exacerbated by the elicitation of Th2 skewed immune responses. Some examples of such disorders and diseases are atopic disorders, pulmonary eosinophilia, eczema, dermatitis, and allergic rhinitis.
Asthma affects approximately 8-10% of the US population, is the leading cause of hospitalization among children less than 15 years of age, and costs society billions of dollars annually (Elias et al., 2003). Despite its public health and economic significance, there are relatively few novel therapies and strategies with proven efficacies available for clinical management of asthmatic patients (Lazaar and Panettieri, 2004, Weinberger, 2004). Although current standard therapies, inhaled bronchodilators (β2 receptor agonists) and anti-inflammatory drugs (corticosteroids), provide effective symptomatic control for the majority of asthma patients, they are sometimes accompanied by certain side effects, particularly in children and in patients with severe asthma requiring high-dose treatments (Lazaar and Panettieri, 2004). Moreover, these therapies require long-term daily administration, and they do not target the underlying immune mechanisms causing allergic asthma (Lazaar and Panettieri, 2004).
The rapid increase in asthma incidence in both the developed and developing countries over the past few decades, suggests that certain environmental, in addition to genetic, factors may contribute to the development of allergic asthma (Strachan, 1989). In this regard, increasing epidemiological and clinical data have suggested that a lack of early childhood exposure to microbial stimulation could favor the development of allergic diseases in genetically predisposed individuals (hygiene hypothesis) (Strachan, 1989). As asthma and allergic airway diseases are disorders associated with a predominant Th2 immune response, suppression of the aberrant allergen-specific Th2 response through antagonism or the induction of regulatory T cells by certain microbes and their products, particularly during neonatal and early childhood periods, may shift the immune response towards a Th1 phenotype and thereby prevent the development of and/or alleviate the clinical symptoms of allergic airway disease (Erb et al., 1998, Hansen et al., 2000, Kline et al., 2002, Matricardi et al., 2003). Indeed, recent experimental and clinical studies have supported the notion that immunization with certain microbes and their products can reduce asthma-like responses (Ennis et al., 2005, Erb et al., 1998, Hansen et al., 2000, Jain et al., 2003, Kim et al., 2004, Kline et al., 2002, Matricardi et al., 2003, Rodriguez et al., 2003, Sayers et al., 2004, Smit et al., 2003, Wohlleben et al., 2003). However, not all microbe-elicited Th1-biased host responses can alleviate the asthma-like symptoms (Schwarze et al., 1997), and some (e.g. Bordetella pertussis, respiratory syncytial virus) may exacerbate airway hyperresponsiveness under certain circumstances (Ennis et al., 2004). On the other hand, systemic immunization with heat-killed whole-cell B. pertussis inhibits allergic airway reactions (airway eosinophilia, lung inflammation and airway hyperresponsiveness)(Kim et al., 2004), despite the fact that both B. pertussis infection and immunization with heat-killed B. pertussis cells induce Th1 immune response (Ennis et al., 2004, Kim et al., 2004). Hence, it is impossible to rationally predict the potential effect of different Th1 response-eliciting microbes and their components on the allergic airway disease. Research results to date have led to suggestions that inhibition of airway eosinophilia maybe limited to mycobacterial infections which induce strong and sustained IFN-γ responses in the lungs (Erb et al., 1998). In the case of the use of M. bovis BCG in suppression of airway eosinophilia, an intranasal (i.n.) dose of 2×103 cfu was ineffective and a dose of 2×105 appeared to be optimal (Erb et al., 1998). However, mycobacterial infections involve a wider array of complex interactions involving proteins, unmethylated DNA, and cell wall components such as lipoglycans, phosphatidylinositol mannan (PIM) and lipoarabinomannan (LAM), which can modulate the host immune responses (Sayers et al., 2004). The use of molecules such as PIM isolated from organisms such as mycobacteria have been described for applications in alleviating Th2-mediated disorders/diseases (Severn et al., 2002). Additionally, heat-killed mycobacteria also suppress allergic airway disease (Sayers et al., 2004). The role of IFN-γ in suppression of airway hyperresponsiveness is confounded by the observation that the IFN-γ levels in asthmatic patients was in fact higher than in the normal cohorts (Cembrzynska-Nowak et al., 1993, Cho et al., 2002). The effect of mycobacterial infections on IgE and IgG1 isotype switching is not clear and contradictory, since some reports indicate that this occurs, whereas others show that it does not (Erb et al., 1998, Matricardi et al., 2003, Sayers et al., 2004). Although previous studies have demonstrated the ability of a number of microbes, including mycobacterial infections, and their products to modulate the course of allergic asthma in the mouse model, many of these treatments were only successful if initiated prior to OVA sensitization or immediately before airway challenge (Erb et al., 1998, Kim et al., 2004, Major et al., 2002).